This application proposes to implement and extensively validate a new computational approach for analyzing anatomical structures in the brain using magnetic resonance imaging. This approach, called the continuous medial representation, is an innovative method that uses the shape of anatomical structures to characterize atrophy and to provide a natural coordinate system in which image information from multiple subjects in a population study can be combined with greater accuracy and higher statistical power than previously possible. The approach differs significantly from existing techniques that consider the brain as a whole, which necessarily limits the sensitivity and specificity of analyses on particular structures of interest. Preliminary results provide compelling support for the elegance of the approach and for its potential to conduct detailed studies of both anatomical and functional effects of disease and injury. [unreadable] The specific aims of the proposal are (1) to verify that cm-rep models can represent the hippocampus accurately, particularly in the presence of pathology; (2) to validate cross-subject normalization via the cm-rep method by examining how well it aligns hippocampal sub-fields; (3) to confirm preliminary findings indicating that shape-based normalization can improve the statistical power of group fMRI analysis; (4) to demonstrate that the cm-rep approach presents an improvement over volume-based and boundary-based methods for combined statistical analysis of hippocampal shape and multivariate/multimodal imaging data. These aims will be achieved by applying the new technique to simulated and real imaging data from functional and structural studies involving temporal lobe epilepsy, Alzheimer's disease, and schizophrenia. This exploratory research, if successful, will clear the ground for a number of follow-up hypothesis-driven research studies addressing structural hippocampal abnormalities and functional recruitment of the hippocampus in memory tasks in various clinical populations. The specific aims of this proposal can have an immediate impact on studies of the hippocampus in health and disease. The hippocampus, whose function involves encoding and consolidating new memories, is of central importance in some of the most common neurological disorders, including epilepsy and dementia. Refined analysis with the new approach proposed in this application promises to impact our understanding of these devastating disorders by detecting and pinpointing smaller, more focal changes in hippocampal anatomy and function than the current methods allow. [unreadable] [unreadable]